PERIODONTAL DISEASE:ROLE OF ABERRANT Ig GLYCOSYLATION

牙周疾病：异常 Ig 糖基化的作用

• 批准号: 6648474
• 负责人: JIRI F MESTECKY
• 金额: $ 29.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6648474
• 关键词: PERIODONTAL; DISEASE; ROLE; ABERRANT; Ig

DESCRIPTION (provided by applicant): Periodontal disease (PD) shares many common features with other human chronic inflammatory disease, such as rheumatoid arthritis, including production of autoantibodies, infiltration of lesions with plasma cells producing mainly IgG, and aberrant glycosylation of IgG-linked glycans. Particularly striking is the deficiency of galactose (Gal) in N-linked glycan side-chains on IgG molecules. Glycans have a profound effect on the biological activities of immunoglobulins (Ig). Deficiency of Gal residues renders such molecules pathogenic due to the fact that terminal N-acetylglucosamine residues, normally covered by Gal, became exposed and are recognized by the ubiquitous mannose-binding lectin resulting in the activation of complement with all the inflammatory consequences resulting in tissue damage. Based on considerable literature reports and our preliminary data, we propose to test the hypothesis that Ig-producing cells found in abundance in mononuclear cell infiltrates in PD secrete Ig molecules with aberrant glycosylation pattern of their glycan moieties. This in turn alters the biological properties of such Ig molecules with respect to their ability to activate complement and to interact with Fc receptors expressed on phagocytic cells resident in the inflamed lesions. Reduced glycosylation of Ig is likely to be due to the effect of cytokines locally produced by several cell types found in inflammatory lesions. Therefore, we propose the following Specific Aims: 1) Characterize the pattern of glycosylation aberrancies of Ig molecules in PD patients by reactivity with lectins highly specific for component monosaccharides and by direct carbohydrate analyses. 2) Determine the origin of aberrantly glycosylated Ig molecules by comparing glycosylation patterns of Ig in serum and lesions to determine whether Ig molecules with altered glycosylation are produced locally in the inflammatory lesions. 3) Determine if the aberrantly glycosylated Igs are specific for antigens of selected bacteria associated with PD. 4) Study mechanisms possibly involved in synthesis of Gal-deficient Ig in PD patients and the biological activities of Ig molecules with altered glycans. Results of these studies will generate information concerning previously unexplored inflammatory pathways that participate in the development of PD.

描述（申请人提供）：牙周病（PD）与其他人类慢性炎症性疾病（例如类风湿性关节炎）有许多共同特征，包括自身抗体的产生、主要产生 IgG 的浆细胞浸润病变以及 IgG 连接的异常糖基化聚糖。特别引人注目的是 IgG 分子的 N 连接聚糖侧链中缺乏半乳糖 (Gal)。聚糖对免疫球蛋白 (Ig) 的生物活性具有深远的影响。 Gal残基的缺乏使得这些分子具有致病性，因为通常被Gal覆盖的末端N-乙酰氨基葡萄糖残基变得暴露并被普遍存在的甘露糖结合凝集素识别，导致补体激活，从而导致组织中的所有炎症后果。损害。基于大量文献报告和我们的初步数据，我们建议检验以下假设：PD 中单核细胞浸润中大量发现的 Ig 产生细胞分泌的 Ig 分子的聚糖部分糖基化模式异常。这反过来又改变了此类 Ig 分子的生物学特性，即它们激活补体并与发炎病变中的吞噬细胞表达的 Fc 受体相互作用的能力。 Ig 糖基化的减少可能是由于炎症病变中发现的几种细胞类型局部产生的细胞因子的作用所致。因此，我们提出以下具体目标： 1) 通过与单糖成分高度特异性的凝集素的反应性以及直接碳水化合物分析来表征 PD 患者中 Ig 分子的糖基化异常模式。 2)通过比较血清和病灶中Ig的糖基化模式来确定糖基化异常的Ig分子的来源，以确定糖基化改变的Ig分子是否在炎症病灶局部产生。 3) 确定异常糖基化 Igs 是否对与 PD 相关的选定细菌的抗原具有特异性。 4) 研究PD患者Gal缺陷型Ig合成可能涉及的机制以及聚糖改变的Ig分子的生物活性。这些研究的结果将产生有关先前未探索的参与帕金森病发展的炎症途径的信息。